The enhanced protective effects of salvianic acid A: A functionalized nanoparticles against ischemic stroke through incr
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The enhanced protective effects of salvianic acid A: A functionalized nanoparticles against ischemic stroke through increasing the permeability of the blood-brain barrier Yaru Li1,2, Xiaojie Zhang1, Zhifeng Qi3 (), Xueling Guo1,2, Xiaopeng Liu4, Wenjuan Shi3, Yang Liu1,2 (), and Libo Du1,2 () 1
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, 100190, Beijing, China 2 Graduate School, University of Chinese Academy of Sciences, Beijing 100049, China 3 Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Captital Medical University, Beijing 100053, China 4 Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050051, China © Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 3 May 2020 / Revised: 7 June 2020 / Accepted: 8 June 2020
ABSTRACT Ischemic stroke is the leading cause of disability and death worldwide. Currently, the only proven treatment for ischemic stroke is restoring the cerebral blood supply. In addition, some of the tissue is damaged during the subsequent reperfusion because of the overproduction of reactive oxygen species (ROS). Furthermore, antioxidant therapies have shown promise in preclinical studies for the treatment of ischemia-reperfusion injury. However, their therapeutic efficacy has been limited because of their low bioavailability in brain. To resolve this issue, we synthesized ROS-responsive, fan-shaped dendrimer nanoparticles (NPs) and conjugated them with a blood-brain barrier (BBB)-targeting peptide, COG1410, and salvianic acid A (SA), which is an effective antioxidant in ischemic stroke. The BBB targeting peptide acts as a ligand of the nanocarrier system and penetrates the BBB through the endocytosis of the ligand receptor. The results showed that T-SA-NPs not only target and accumulate in the infarct area, they also reduce over 2 times of the infarct area and reverse the behavioral deficits in MCAO mice, which illustrates that these NPs have an effective therapeutic effect on the ischemic stroke. In addition, these NPs had no toxicity in any organs of the body. Importantly, the present study provides an alternative strategy for delivering antioxidants to the brain and achieving targeted therapy of ischemic stroke.
KEYWORDS ischemic stroke, blood-brain barrier, salvianic acid A, COG1410, reactive oxygen species (ROS)-responsive nanocarrier, mitophagy
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Introduction
Stroke, which is an acute cerebrovascular disease with high mortality and morbidity, ranks fifth among all causes of death. In addition, stroke is generally divided into hemorrhagic stroke and ischemic stroke [1]. Accounting for about 85% of strokes, ischemic strokes are usually a result of a cerebral infection. The main treatment for ischemic stroke is intravenous thrombolysis that is administered within 3 h after the stroke and it is considered to be the only effective treatment to restore the blood supply to t
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